The ascending aorta experiences unique multiaxial loading during each cardiac cycle: finite distension due to changes in blood pressure plus finite extension, torsion, and bending due to the direct action of the beating heart. We hypothesize that this unique, cyclic multiaxial loading coupled with the unique underlying micro- structure and cell lineage of the ascending aorta accelerates a mechano-aging process that manifests as the recently reported earliest reductions in distensibility and wall strain and the earliest and mot dramatic increases in length of any segment of the human aorta. We hypothesize further that heritable connective tissue disorders that commonly lead to aneurysms of, and dissections in, the aortic root or ascending aorta also tend to manifest first in this region of the aorta because they accelerate this mechano-aging process. A singularly important histopathological feature of this aging process is an increased accumulation, and at times pooling, of glycosaminoglycans, the mechanical implications of which have never been studied. The two goals of this R03 application are: (1) Build a next generation computational (finite element) mixture model of the ascending aorta that embodies the unique biomechanics: multiaxial loading, regionally varying residual stresses and nonlinear material properties that off-set regional variations in geometry to give rise to mechanical homeostasis in normalcy, and pre-mature alterations in elastic fibers, smooth muscle, fibrillar collagens, and most importantly glycosaminoglycans (via a Donnan swelling pressure); and (2) Inform and validate the finite element model using data from wild-type and fibulin 5 null mice. Data will include microCT information on the overall geometry, ultrasound information on local blood flow, nonlinear material properties measured using custom in vitro biaxial testing, residual stress related measurements of opening angles, and histo-morphological measures of regional wall thicknesses and composition. This proposal is submitted under the R03 mechanism for it focuses primarily on the development of research methodology (i.e., a nonlinear constrained mixture constitutive relation for the ascending aorta that accounts for the first time for progressive losses of elastic fiber integrity, pooling of GAGs PGs, and remodeling of collagen that results in accelerated aging), the development of new research technology (i.e., the first open source finite element model capable of modeling the unique evolving histo-mechanics of the ascending aorta), and pilot or feasibility studies (i.e., initial validation studies using fibulin 5 null mice, which show accelerated aging). We submit that development of the proposed, next generation computational model of the ascending aorta will enable much more realistic studies by ourselves and (via resource sharing) others to elucidate underlying biomechanical causes of thoracic aortic aneurysms and dissections, diminished left ventricular function due to stiffening of the aorta, and deleterious systemic hemodynamics as well as an improved design of surgical procedures or grafts.